IgE secretion is attenuated by an inhibitor of proteolytic processing of CD23 (Fc epsilonRII).
CD23, the low-affinity IgE receptor, is up-regulated on interleukin (IL)-4-stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by proteolytic processing of the surface-bound intact CD23. The effect of inhibition of the processing of CD23 on IgE production in human and mouse cells and in a mouse model in vivo was evaluated. CD23 processing to sCD23 from RPMI 8866 (a human Epstein-Barr virus-transformed B cell line) cell membranes was inhibited by a broad-spectrum matrix-metalloprotease inhibitor, batimastat, with an IC50 of 0.15 microM. Batimastat also inhibited CD23 processing in whole RPMI 8866 cells as well as in IL-4-stimulated purified human monocytes with similar IC50. Batimastat inhibited IgE production from IL-4/anti-CD40-stimulated human tonsil B cells as well as mouse splenic B cells in a manner consistent with inhibition of CD23 processing. Release of soluble fragments of CD23 in the cell supernatants of tonsil B cells was inhibited over the concentration range of 1-10 microM batimastat and intact cell surface CD23 was increased on mouse splenic B cells in the presence of these concentrations of batimastat. IgE production of IL-4-stimulated human peripheral blood mononuclear cells was also blocked by 1-10 microM batimastat, again with comparable inhibition of sCD23 release over the same concentration range. Finally, in a mouse model of IgE production, batimastat inhibited IgE production in response to ovalbumin challenge as determined by serum IgE levels. Taken together, the data support a role of CD23 in IgE production and point to CD23 processing to sCD23 as a therapeutically relevant control point in the regulation of IgE synthesis.
Christie
G
G
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park North, Harlow, GB.
Barton
A
A
Bolognese
B
B
Buckle
D R
DR
Cook
R M
RM
Hansbury
M J
MJ
Harper
G P
GP
Marshall
L A
LA
McCord
M E
ME
Moulder
K
K
Murdock
P R
PR
Seal
S M
SM
Spackman
V M
VM
Weston
B J
BJ
Mayer
R J
RJ
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002461:Cell Line, Transformed; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D017455:Receptors, IgE / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013876:Thiophenes / Q000494:pharmacology*
D011480:Protease Inhibitors; D017455:Receptors, IgE; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat